mt_monashmedfandomcom-20200213-history
L0301P32 - Mutations and Single Gene Disorders
Definitions *gene **the basic unit of information *locus **location of a gene on a chromosome and is constant for a given gene *allele **an alternative form of a gene found at the same locus on homologous chromosomes *homozygous **presence of two identical alleles at a given locus on a pair of homologous chromosomes *heterozygous **presence of different alleles at the same locus on a pair of homologous chromosomes Mutations *heritable changes of the genetic material *may occur in coding (cause effects) and non-coding (typically no effects) regions *can be: **induced: exposure to mutagenic agents (chemicals and radiation) **spontaneous: errors in DNA replication and repair mechanisms Somatic Mutations *occurs in non-gamete body cells **may be passed by mitosis to all subsequent somatic cell generations of the particular cell line Germ line Mutations *occurs in cells which give rise to gametes **are passed on to offspring Silent Mutations *do not affect protein function Loss of Function Mutation *affects protein function and may lead to structural proteins that no longer work *almost always recessive Gain of Function Mutation *lead to a protein with altered function *dominant disorder - Cancers, Huntington Conditional Mutations *causes phenotype changes only under restrictive conditions *not detectable under permissive conditions Mutations on a Molecular Level Point Mutations *gain, loss, substitution of a single nucleotide *silent, missense, nonsense, frameshift Chromosomal Mutations *more extensive *may change position of cause a DNA segment to be duplicated or lost ---- Point Mutations Silent Mutations *no effect on protein because **of redundancy of genetic code (wobble) **occur in non-coding regions *results in genetic diversity - not expressed as phenotype differences - polymorphisms Missense Mutations *often in 1st and 2nd bases of codon *will alter protein but to different degrees **no change in function **reduced protein efficiency **complete loss of function *e.g. sickle cell disease - glu-val mutation Nonsense Mutations *premature termination - causes a stop codon early in the protein Frameshift Mutations *insertion or deletion *all amino acids changed past insertion/deletion point *may create deleterious protein but more often than not, just a useless protein ---- Chromosomal Mutations Deletions *severe consequences, unless affecting non-coding DNA, unnecessary genes or masked by normal alleles Duplication *homologous chromosomes break in different places and recombine with wrong partners leaving two copies of a particular segment Inversions *results from breaking and joining but segment is flipped Translocation *segment of DNA breaks off and is inserted into another chromosome, can cause duplications and deletions *may result in sterility if chromosome pairing is impossible *meiosis is interrupted Affects of Intron Mutations Mutations in introns can still affect the body *may cause spliceosomes to not be able to recognise introns and exons causing incorrect mRNA made Pros and Cons of Mutations Pros *provide raw material for evolution *mutation can improve organisms adaptation to its environment or become favourable as conditions change Cons *can harm the organism or be neutral Haemoglobinopathies *series of disorders relating to the structure and/or the synthesis of haemoglobin (Hb) *most common single gene disorders **up to 10% of the world’s population are carriers of these mutations **marked difference in carrier rates between different populations *possible disorders **structural variants **diminished synthesis of global chains **abnormal association of normal subunits Structure of Haemoglobin *tetramer ** 2 α chains and 2 β chains Structural Variants *Haemolytic anemia: **Sickling disorder (HbS) **Unstable Hb (Hb Gun Hill, Hb Bristol) *Cyanosis: **Methemoglobinemia (HbM) **Low oxygen affinity (Hb Kansas) *Polycythemia: **High oxygen affinity (Hb Chesapeake) Sickle-Cell Disease *most common Hb disease *autosomal recessive *missense mutation in human β-globin *changes one amino acid - glu to val *advantage for carriers (heterozygotes) **resistant to malaria parasite (cannot live inside the RBC) Thalessemia *most common single group of inherited disorders *imbalance of globin chain production **precipitation of chains resulting in haemolysis of RBCs Alpha Thalessmia *under/abnormal production of α globin chains *deletion of α-genes or nonsense mutations *can be fatal Beta Thalessmia *reduced or absent β chains